Effects of the antihistaminergic drugs diphenhydramine and zolantidine on vestibular-induced hypothalamic neuronal activity in the guinea pig.

The mode of action of diphenhydramine in treating motion sickness is unknown. Using an electrophysiologic technique, we investigated the effects of intravenous diphenhydramine and zolantidine on the changes in neuronal activity produced by caloric stimulation in the hypothalamic paraventricular nucleus (PVN) in the guinea pig. Changes in neuronal activity were modulated by the administration of diphenhydramine in a high percentage of the neurons tested (71%), while zolantidine affected only a small number (29%). This finding reinforces the involvement of a histaminergic system in vestibular autonomic responses. The modulatory effect of diphenhydramine on PVN neuron activity may explain in part this drug's efficacy in treating motion sickness.

Comparison of survival rates of patients with nasopharyngeal carcinoma treated with radiotherapy, 5-fluorouracil and vitamin A ("FAR" therapy) vs FAR therapy plus adjunctive cisplatin and peplomycin chemotherapy.

The overall survival rate (OSR) of 36 patients with nasopharyngeal carcinomas (NPC) treated at Kyushu University hospital between 1983 to 1992 was analyzed. As primary treatment, 16 patients received a combination therapy of 5-fluorouracil, vitamin A, and radiation (FAR therapy); two patients received radiotherapy only; 18 patients received FAR therapy plus adjunctive systemic chemotherapy consisting of cisplatin and peplomycin. The radiation dose to the nasopharynx was 6000 to 7050 cGy while that to the neck was 4000-6000 cGy. The 5-year OSR of all the patients was 49%. Histological type (moderately differentiated squamous cell carcinoma) and patient age (> or = 55) were found to be significant prognostic factors for a worse OSR. Although survival decreased with increasing T stage, no significant difference was observed. The 5-year OSR of the patients treated with FAR therapy was 53% and was 51% with FAR therapy plus chemotherapy. Compared to FAR therapy alone, adjunctive chemotherapy did not increase OSR of the patients with NPC.

Convergence of olfactory and nasotrigeminal inputs and possible trigeminal contributions to olfactory responses in the rat thalamus.

To elucidate the role of trigeminal input on the olfactory system, field-evoked potentials were measured following electrical stimulation of the nasociliary branch of the trigeminal nerve in the olfactory-related structures in the rat brain. Significant potential changes were recorded in the mediodorsal nucleus of the thalamus and the lateral hypothalamic area. In the mediodorsal nucleus of the thalamus, the neurons responding to olfactory bulb electrical stimulation also responded to trigeminal nerve stimulation. Single neuronal responses of mediodorsal thalamic neurons following odorant stimulation were enhanced by blockade of the trigeminal nerve with procaine. These results suggest that olfactory and trigeminal pathways converge on the same neural elements within the mediodorsal nucleus of the thalamus and that the trigeminal input may modulate olfactory input in this nucleus.

Effects of sleep-promoting substance on rat hypothalamic neuron activity.

The effects of electrophoretically applied sleep-promoting substance (SPS) on neuronal activity of the preoptic area (POA) and SPS interactions with some neurotransmitters were examined in the rat. In the POA, 14% of the tested neurons were excited and 13% were inhibited by SPS. Neurons that were excited by SPS were also excited by glutamate (Glu). The excitatory effect of Glu was blocked or attenuated by concurrent application of SPS in 35% of the neurons, and this modulatory effect was long-lasting. A significant number of SPS responsive neurons were inhibited by noradrenaline (NA). This inhibitory effect was attenuated, blocked or reversed by concurrent application of SPS in 28% of the tested neurons. There was no relation between the effects of acetylcholine (ACh) alone and those of SPS alone. The effects of ACh were modified by concurrent SPS application in 21% of the neurons tested; the effect was either enhancement or blockade of the ACh excitation. Possible contribution of SPS in the hypothalamus to the regulation of sleep and wakefulness is discussed.

Effects of prostaglandin D2 on the activity of hypothalamic neurons in the rat.

The effects of electrophoretically applied prostaglandin D2 (PGD2) on neuronal activity in the rat lateral preoptic area (LPOA) and posterior hypothalamic area (PHA) were examined. In the LPOA, 20% of the tested neurons were excited, 26% inhibited, and 6% showed bidirectional response. The direct effects often showed desensitization after repeated applications. Neurons excited by PGD2 were significantly sensitive (excitation) to acetylcholine (ACh). The ACh excitatory effect was sometimes (38%) attenuated, blocked, or reversed by concurrent PGD2 application. Excitatory or inhibitory effect of noradrenaline (NA) was not related to the effects of PGD2; however, modulation of the NA responses by PGD2 was common (58%). Inhibition, the predominant NA response, was changed to no effect or to excitation during simultaneous PGD2 application. Changes of the NA responses from inhibition to excitation, or from excitation to inhibition-excitation sequences were observed after PGD2 infusion into the third cerebral ventricle at low concentrations. In 43% of the cells, neurotransmission in the LPOA following ventral noradrenergic bundle stimulation was modified by PGD2 application. PGD2 application tended to reduce the duration of inhibition and to extend that of excitation. The direct effects of PGD2 in the PHA were similar to those in the LPOA. Desensitization was also observed in the PHA, but no interrelations were observed among the effects of PGD2, ACh, and NA. Modulation of ACh and NA responses by PGD2 was rarely seen in the PHA. Possible contributions of PGD2 to sleep and thermoregulation are discussed.

Glucagon-related peptides in the rat hypothalamus.

Immunohistochemically, nerve fibers and terminals reacting with anti-N-terminal-specific but not with anti-C-terminal-specific glucagon antiserum were observed in the following rat hypothalamic regions: paraventricular nucleus, supraoptic nucleus, anterior hypothalamus, arcuate nucleus, ventromedial hypothalamic nucleus and median eminence. Few fibers and terminals were demonstrated in the lateral hypothalamic area and dorsomedial hypothalamic nucleus. Radioimmunoassay data indicated that the concentration of gut glucagon-like immunoreactivity was higher in the ventromedial nucleus than in the lateral hypothalamic area. In food-deprived conditions, this concentration increased in both these parts. This was also verified in immunostained preparations in which a marked enhancement of gut glucagon-like immunoreactivity-containing fibers and terminals was observed in many hypothalamic regions. Several immunoreactive cell bodies were found in the ventromedial and arcuate nuclei of starved rats. Both biochemical and morphological data suggest that glucagon-related peptides may act as neurotransmitters or neuromodulators in the hypothalamus and may be involved in the central regulatory mechanism related to feeding behavior and energy metabolism.

Central action of glucagon in rat hypothalamus.

The effects of electrophoretically applied glucagon on neuronal activity in the rat lateral hypothalamic area (LHA), dorsomedial hypothalamic nucleus (DMH), and ventromedial hypothalamic nucleus (VMH) were examined. In the LHA glucagon significantly suppressed the activity of glucose-sensitive neurons compared with its effect on non-glucose-sensitive neurons. This inhibitory effect of glucagon on LHA neurons was blocked by ouabain. Intracellular recordings from LHA neurons revealed that glucagon hyperpolarized the cell membrane without a significant change in the input membrane resistance. Intra-arterial injection of glucagon suppressed the activity of some neurons that were suppressed by electrophoretically applied glucagon. Similarly, glucagon suppressed the activity of significant numbers of DMH and VMH neurons with doses higher than those that affected LHA glucose-sensitive neurons. Cortical neurons were unaffected by glucagon. The data suggest that blood-borne glucagon could suppress the activity of LHA glucose-sensitive neurons and, in addition, might contribute to the control of metabolism and the termination of feeding behavior.

Effect of intracerebroventricularly infused glucagon on feeding behavior.

Administration of pancreatic glucagon into 3rd cerebral ventricle of rats suppressed feeding with potency greater than 1000 times that of peripheral administration. A low dose of glucagon (5 ng) suppressed food intake mainly in short-term and slightly in long-term. A medium dose (25 ng) produced delayed feeding suppression. A high dose (100 ng) suppressed only short-term food intake. From this evidence, it is concluded that intracerebroventricular administration of physiological concentration of pancreatic glucagon suppresses short-term food intake through the hypothalamus. The possible mechanism of feeding suppression by glucagon is discussed.